Process for producing (dioxolenon-4-yl)methyl ester derivative

Abstract

There is provided a method by which various compounds (1) having a carboxyl group in the molecule have the carboxyl group converted to a (dioxolenon-4-yl)methyl ester at low cost, in a simple way and at high yield. The process for producing compounds of formula (3) according to the reaction scheme shown below comprises reacting carboxylic acids of formula (1) with 4-chloromethyldioxolenone compounds of formula (2) in a solvent in the presence of both a phase transfer catalyst and a metal iodide: [where Q represents an organic group, M represents a hydrogen atom, an alkali metal, an alkaline earth metal or a transition metal, R 1 and R 2 represent a hydrogen atom, an optionally substituted (C 1-6 alkyl group or phenyl group)].

1. A process for producing a (dioxolenon-4-yl)methyl ester derivative of formula (3) 
       
         
           
           
               
               
           
         
       
       (where Q represents the fused heterocyclic group having a β-lactam ring of the following formulae: 
       
         
           
           
               
               
           
         
       
       where r 1  and r 4  represent a 1-hydroxyethyl group or an optionally substituted benzoylamino group; r 2 , r 5,  r 6 , r 7  and r 8  each independently represent hydrogen or a C 1-6  alkyl group that may be optionally substituted by G 1 ; a C 2-6  alkenyl group that may be optionally substituted by G 1 ; a C 2-6  alkynyl group that may be optionally substituted by G 1 ; a tetrahydrofuranyl and a heterocyclic group that may optionally be substituted by G 1 ;
 G 1  represents a nitro group; a cyano group; a halogen atom; a C 1-6  alkoxy group; a C 1-6  alkylthio group; a C 1-6  alkylsulfinyl group; a C 1-6  alkylsulfonyl group; a C 1-6  alkylamino group; a di-C 1-6  alkylamino group; a C 1-6  alkylcarbonyl group; a C 1-6  alkoxycarbonyl group; an optionally G 2  substituted phenylsulfinyl group; an optionally G 2  substituted phenylsulfonyl group; an optionally G 2  substituted phenylthio group; 
 G 2  represents a halogen atom; a C 1-6  alkyl group; a C 1-6  haloalkyl group; or a C 1-6  haloalkoxy group; and 
 R 1  and R 2  each independently represent a hydrogen atom, an optionally substituted C 1-6  alkyl group or an optionally substituted phenyl group, provided that R 1  and R 2  may combine to form an optionally substituted ring having 3–8 carbon atoms) by reacting a carboxylic acid derivative of formula (1) 
 
       
         
           
           
               
               
           
         
       
       (where Q has the same meaning as defined above, M represents a hydrogen atom, an alkali metal, an alkaline earth metal or a transition metal, and n represents the atomic valency of M)
 with a 4-chloromethyldioxolenone compound of formula (2) 
 
       
         
           
           
               
               
           
         
       
       (where R 1  and R 2  have the same meanings as defined above) in a solvent in the presence of both a phase transfer catalyst and a metal iodide. 
     
     
       2. A process for producing a (dioxolenon-4-yl)methyl ester derivative of formula (3) 
       
         
           
           
               
               
           
         
       
       (where Q represents the fused heterocyclic group having a β-lactam ring of the following formulae: 
       
         
           
           
               
               
           
         
       
       where r 1  and r 4  represent a 1-hydroxyethyl group or an optionally substituted benzoylamino group; r 2 , r 5 , r 6 , r 7  and r8 each independently represent hydrogen or a C 1-6  alkyl group that may be optionally substituted by G 1 ; a C 2-6  alkenyl group that may be optionally substituted by G 1 ; a C 2-6  alkynyl group that may be optionally substituted by G 1 ; a tetrahydrofuranyl and a heterocyclic group that may optionally be substituted by G 1 ;
 G 1  represents a nitro group; a cyano group; a halogen atom; a C 1-6  alkoxy group; a C 1-6  alkylthio group; a C 1-6  alkylsulfinyl group; a C 1-6  alkylsulfonyl group; a C 1-6  alkylamino group; a di-C 1-6  alkylamino group; a C 1-6  alkylcarbonyl group; a C 1-6  alkoxycarbonyl group; an optionally G 2  substituted phenylsulfinyl group; an optionally G 2  substituted phenylsulfonyl group; an optionally G 2  substituted phenylthio group; 
 G 2  represents a halogen atom; a C 1-6  alkyl group; a C 1-6  haloalkyl group; or a C 1-6  haloalkoxy group; and 
 R 1  and R 2  each independently represent a hydrogen atom, an optionally substituted C 1-6  alkyl group or an optionally substituted phenyl group, provided that R 1  and R 2  may combine to form an optionally substituted ring having 3–8 carbon atoms) 
 by reacting a carboxylic acid of formula (5) 
 
       
         
           
           
               
               
           
         
       
       (where Q has the same meaning as defined above) with a 4-chloromethyldioxolenone compound of formula (2) 
       
         
           
           
               
               
           
         
       
       (where R 1  and R 2  have the same meanings as defined above) in a solvent in the presence of both a quaternary ammonium hydroxide of the formula: R a R b R c R d NOH 
       (where R a –R d  each independently represent a C 1-20  alkyl group or a C 7-20  aralkyl group) and a metal iodide. 
     
     
       3. The process for producing a (dioxolenon-4-yl)methyl ester derivative of formula (3) according to  claim 1  or  2 , wherein a polar solvent is used as said solvent. 
     
     
       4. The process for producing a (dioxolenon-4-yl)methyl ester derivative of formula (3) according to any one of  claims 1 – 2 , wherein said metal iodide is used in an amount of 5–20 mol % of the 4-chloromethyldioxolenone compound of said formula (2). 
     
     
       5. The process for producing a (dioxolenon-4-yl)methyl ester derivative of formula (3) according to any one of  claims 1 – 2 , wherein an alkali metal iodide is used as said metal iodide. 
     
     
       6. The process for producing a (dioxolenon-4-yl)methyl ester derivative of formula (3) according to  claim 1 , wherein a quaternary ammonium salt is used as said phase transfer catalyst. 
     
     
       7. The process for producing a (dioxolenon-4-yl)methyl ester derivative of formula (3) according to  claim 6 , wherein a benzyltrialkylammonium halide is used as said quaternary ammonium salt. 
     
     
       8. The process for producing a (dioxolenon-4-yl)methyl ester derivative of formula (3) according to any one of  claims 1 – 2 , wherein a base is further added at least in an amount corresponding to the amount of the acidic impurities contained in the 4-chloromethyldioxolenone compound represented by said formula (2). 
     
     
       9. The process for producing a (dioxolenon-4-yl)methyl ester derivative of formula (3) according to any one of  claims 1 – 2 , wherein the reaction is performed by elevating the reaction temperature through a plurality of stages. 
     
     
       10. The process for producing a (dioxolenon-4-yl)methyl ester derivative of formula (3) according to  claim 9 , wherein the reaction is performed by elevating the reaction temperature in two stages, the first stage at 40° C. or below and the second stage at 50° C. or above. 
     
     
       11. The process for producing a (dioxolenon-4-yl)methyl ester derivative of formula (3) according to any one of  claims 1 – 2 , wherein the reaction is performed in a solvent selected from THE, DMF, DMSO or acetone. 
     
     
       12. The process for producing a (dioxolenon-4-yl)methyl ester derivative of formula (3) according to  claim 11 , wherein the solvent is THF.